Nasal drug delivery device

ABSTRACT

A compound delivery device for delivering a plume derived from a propellant and a drug formulation. The drug formulation is in an intranasal dosage form in the form of powder, suspension, dispersion or liquid. The propelled intranasal dosage form is deposited within the olfactory region of the nasal cavity. The drug deposited within the olfactory region is delivered to the brain avoiding the blood-brain-barrier. Hydrofluoroalkane propellant from a pressurized canister is channeled to a diffuser and drug-containing chamber where the intra-nasal dosage form is aerosolized. The aerosolized intra-nasal dosage form passes through a nozzle thus delivering a plume to the olfactory region of a user&#39;s nasal cavity.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/338,097, filed on Oct. 28, 2016, (now U.S. Pat. No. 10,507,295),which is a continuation of U.S. patent application Ser. No. 14/017,048,(now U.S. Pat. No. 9,550,036), filed on Sep. 3, 2013, entitled “NasalDrug Delivery Device,” which claims priority to an international patentapplication PCT/US2012/027754, filed Mar. 5, 2012, which claims priorityto U.S. Application No. 61/449,008, filed Mar. 3, 2011, U.S. ApplicationNo. 61/451,935, filed Mar. 11, 2011, U.S. Application No. 61/484,025,filed May 9, 2011, and U.S. Application No. 61/498,974, filed Jun. 20,2011, the entire contents of each priority application are herebyincorporated by reference in their entirety.

STATEMENT CONCERNING GOVERNMENT INTEREST

This invention was made with U.S. government support pursuant to US ArmySBIR grant W81XWH-10-C-0238. The Government may have certain rights inthis application.

BACKGROUND

The central nervous system (CNS) includes the brain, the brain stem, andthe spinal cord. The CNS is isolated from the external world by severalmembranes that both cushion and protect the brain, the brain stem, andthe spinal cord. For example, the membranes that form the blood-brainbarrier (BBB) protect the brain from certain contents of the blood. Theblood-cerebrospinal fluid barrier (BCSFB) protects other portions of theCNS from many chemicals and microbes.

Traditional methods for delivering compounds to the CNS are typicallyinvasive. For example, a pump implanted in the skull, such as anintracerebroventricular pump, can deliver a variety of compounds to thebrain. However, implanting such a pump requires brain surgery, which canentail a variety of serious complications. Certain compounds, forexample epidural painkillers, can be injected directly through theprotective membrane into the CNS. However, such injection is impracticalfor most compounds.

Intranasal administration has traditionally focused on the distributionof drug solutions as a mist for topical delivery to the nasalepithelium. Because of the nasal cavity's easily accessed vascular bed,nasal administration of medications has focused the delivery ofmedications either locally to the nasal cavity or directly to the bloodstream.

Much of the current brain research is focused on the enhancement of thedrug being delivered to the brain by various formulations. Thetraditional approaches to improve uptake of compounds to the brain byformulation enhancement include (1) mucoadhesive formulations; 2)penetration enhancers; 3) liposomes; 4) vasoconstrictors; and 5)nanoparticles. Examples of various compounds with have enhancedformulations include various cytokines, for example, tumor necrosisfactors, interleukins, and interferons discussed in U.S. Pat. No.6,991,785 and growth and differentiation factor-5 (GDF-5) and relatedproteins discussed in US Publication No. 20100074959.

Targeting of drugs to the central nervous system (CNS) is a challengingtask. A great number of drugs, including biotechnology products, arecandidates for treatment of CNS diseases, but drug delivery is a problemfor brain targeting. A limitation in the treatment of brain tumors isthat less than 1% of most therapeutic agents administered systemicallyare able to cross the BBB. The transport of small molecules across theBBB is the exception rather than the rule, and 98% of all smallmolecules do not cross the BBB (Pardride, NeuroRx. 2005 January; 2(1):1-2. 2005); approximately 100% of large-molecule drugs or genes do notcross the BBB (Pardride, NeuroRx. 2005 January; 2(1): 1-2. 2005). TheBBB allows small (about less than 500 Da), lipophilic molecules from thebloodstream to enter the CNS (Pardridge, Arch Neurol. 2002; 59:35-40).Many larger therapeutic agents are prevented from reaching the brain fortreating CNS disorders such as but not limited to Parkinson's disease,Alzheimer's disease, depression, stroke, and epilepsy (Pardridge,NeuroRx. 2005 January; 2(1): 3-14). Disorders including autism,lysosomal storage disorders, fragile X syndrome, ataxis, and blindness,are serious disorders where there is little effective treatment. In manyof these cases, the gene underlying the disease is known, but BBBdelivery is the rate-limiting problem in gene therapy or enzymereplacement therapy, and no therapeutics have been developed. Drugdelivery of therapeutic compounds, for example proteins, faces severalchallenges because of their instability, high enzymatic metabolism, lowgastrointestinal absorption, rapid renal elimination, and potentialimmunogenicity.

There is a need for devices that can deliver compounds to the uppernasal cavity for direct nose-to-brain delivery. Certain existing nasaldrug delivery devices do not adequately propel the drug from the device.Inconsistent propulsion of drug due to inconsistent user actuation isalso far from optimal. Still further, the plume generated by suchexisting devices is too wide. Even further, some drug products do notreadily mix and/or stay suspended with propellants in a MDI type device.Certain existing nasal drug devices rely on circumferential velocity topropel medicaments to the olfactory epithelium. Traditionalcircumferential devices result in a lower percentage of compounddeposited on the olfactory epithelium. A circumferential component inthe aerosol plume tends to result in a wider spray plume with a portionof the aerosol particles targeted to the sides of the nasal cavity inthe lower part of the nasal cavity.

Better mechanisms for administering desired agents to the brain, brainstem, and/or spinal cord are needed.

SUMMARY

A device for delivering a compound to the olfactory region of the nasalcavity is described including a canister capable of containing apropellant, a diffuser in communication with the canister, a compoundchamber in communication with the diffuser, and a nozzle incommunication with the compound chamber, wherein the device is capableof delivering the compound to the olfactory region of the nasal cavity.

In one aspect, the device includes a canister that is pressurized.

In another aspect, the propellant includes HFA, nitrogen, or CFC.

In another aspect, the device includes a compound chamber containing adrug or an imaging agent.

In yet another aspect, the drug is an oxime.

In yet another aspect, the diffuser is a frit.

In yet another aspect, the imaging agent is FDG or FLT.

In yet another aspect, the device includes a propellant, where thepropellant is a pressurized liquid.

In yet another aspect, the pressurized liquid is HFA.

In another aspect, the pressurized liquid HFA is released from thecanister and comes into contact with the diffuser, whereby the diffuserconverts the pressurized liquid HFA to gaseous HFA.

In another aspect, the diffuser converts a minority of the pressurizedliquid HFA to gaseous HFA

In a further aspect, the diffuser converts a majority of the pressurizedliquid FIFA to gaseous HFA.

In yet another aspect, the device delivers at least 62.6% of thecompound to the olfactory region.

In yet another aspect, the device delivers greater than 64.2% of thecompound to the olfactory region.

In another aspect, the device delivers at least 64.3% of the compound tothe olfactory region.

In yet another aspect, the device includes a canister where the canisteris a syringe, syrette, or barrel.

In yet another aspect, the compound is not an imaging agent.

In further aspect, the compound is not FDG.

In one aspect, the drug is in the form of a liquid suspension, a liquiddispersion, a powder, or an aqueous solution.

In yet another aspect, the device further includes an aiming guide.

In yet another aspect, the aiming guide aides in positioning of thenozzle of the device at the user's olfactory region.

In yet another aspect, the devices further includes an insertion port mcommunication with the compound chamber.

In yet another aspect, the device further includes an indicator providedto alert the user to the length or amount of a capsule's insertion intothe user's nasal cavity.

In one aspect, the diffuser is porous.

In another aspect, the diffuser is heterogeneously porous.

In another aspect, the diffuser is homogenously porous.

In another aspect, the diffuser is extended.

In yet another aspect, the diffuser is a disk-shaped member includingconical shaped members having distal apertures.

In yet another aspect, the canister is a metered dose inhaler.

In another embodiment, a device for delivering a compound is describedincluding a canister capable of containing a propellant, a diffuser incommunication with the canister, a compound chamber in communicationwith the diffuser, and a nozzle in communication with the compoundchamber, where the device is capable of delivering the compound to ear,skin, buccal cavity, or eyes.

In another embodiment, a method is described for delivering drug to theolfactory region of the nasal cavity including providing a canistercapable of containing a propellant, a diffuser in communication with thecanister, a compound chamber in communication with the diffuser, and anozzle in communication with the compound chamber, where when actuatedthe device is capable of delivering the compound to the olfactory regionof the nasal cavity.

In one aspect, the method includes the delivery of a drug for thetreatment of an infectious disease, oncology, or immunological disease.

In one aspect, the method includes actuating the device to deliverpropellant from the canister, whereby the diffuser diffuses the liquidpropellant from the canister to a gaseous propellant, the gaseouspropellant contacts the compound in the compound chamber and thecompound and gaseous propellant exits the nozzle of the device.

In another aspect of the method, the diffuser converts a minority of thepressurized liquid HFA to gaseous HFA.

In another aspect of the method, the diffuser converts a majority of thepressurized liquid HFA to gaseous HFA.

In yet another aspect of the method, at least 64.2% of the compound isdelivered to the olfactory region.

In yet another aspect of the method, greater than 64.2% of the compoundis delivered to the olfactory region.

In another aspect of the method, the compound is a drug or diagnosticagent.

In another aspect of the method, the compound is a drug.

In yet another aspect of the method, the diagnostic agent is an imagingagent.

In yet another aspect of the method, the drug is an oxime.

In yet another aspect of the method, the imaging agent isfluorodeoxyglucose or fluorothymidine.

In yet another aspect of the method, the compound is notfluorodeoxyglucose.

In yet another aspect of the method, the compound is not an imagingagent.

In yet another aspect of the method, the drug is in the form of a liquidsuspension, a liquid dispersion, a powder, liposome, or an aqueoussolution and combinations thereof.

In yet another aspect of the method, the device includes one or moreaiming guides.

In yet another aspect of the method, the aiming guide assists m thepositioning of the nozzle of the device at the user's olfactory region.

In another aspect of the method, the device includes an insertion portin communication with the compound chamber.

In an aspect of the method, the device includes an indicator provided toalert the user to the depth of insertion of the device into the user'snasal cavity.

In another aspect of the method, the diffuser is porous.

In another aspect of the method, the diffuser is heterogeneously porous.

In another aspect of the method, the diffuser is homogenously porous.

In an aspect of the method, the diffuser is extended.

In another aspect of the method, the diffuser is a disk-shaped memberincluding conical shaped members having distal apertures.

In an aspect of the method, the canister is a metered dose inhaler.

In another embodiment, an intranasal formulation of an oxime for use intreating exposure to an organophosphate is described.

In yet another embodiment, a method is described for delivering an oximeacross the blood brain barrier to a subject in need thereof includingadministering to the subject a therapeutically effective dosage of anoxime, wherein the dosage is delivered to the upper olfactory region ofthe nasal cavity.

In one aspect of the method, the therapeutically effective amount of anoxime administered to the user is within the range of about 0.001 mg/kgto about 100 mg/kg.

In another aspect of the method, the therapeutically effective amount ofan oxime administered to the user is within the range of about 0.01mg/kg to about 10 mg/kg.

In yet another aspect of the method, the therapeutically effectiveamount of an oxime administered to the user is within the range of about0.1 mg/kg to about 1 mg/kg.

In yet another aspect, the method described for delivering an oxime isfor treatment of organophosphate exposure.

In another embodiment, a method of delivering an oxime intranasally to auser is described including providing a nasal dosage form of the oxime,propelling the nasal dosage form with a propellant, and delivering thenasal dosage form to the nasal cavity of the user, so that the oxime isdelivered to the nasal cavity and subsequently to the central nervoussystem and/or brain of the user.

In one aspect, the oxime delivered includes 2-PAM, MMB4, HI6, TMB4 orHlo7 and combinations thereof.

In another aspect, the nasal dosage form of the oxime is a powder, anaqueous solution, a suspension or a lipid containing product andcombinations thereof.

In another aspect, the user has been exposed to an organophosphate drugincluding sarin, tabun, soman, Russian VX or diisopropylfluorophosphateand combinations thereof.

In another aspect, a majority of the oxime in nasal dosage form isdeposited within the nasal cavity.

In another aspect, a nasal dosage form of a muscarinic receptor agonistor a muscarinic receptor antagonist is delivered intranasally.

In yet another aspect, a nasal dosage form of atropine or scopolamine orcombinations thereof is provided intranasally.

In yet another aspect, a nasal dosage form a benzodiazepine antagonistis provided intranasally.

In yet another aspect, the benzodiazepine antagonist includes diazepam,midazolam or lorazepam or combinations thereof.

In yet another aspect, the nasal dosage form is a benzodiazepineantagonist, a muscarinic receptor agonist or a muscarinic receptorantagonist or combinations thereof.

In yet another aspect, the intranasal dosage form includes diazepam,midazolam, lorazepam, atropine or scopolamine or combinations thereof.

In yet another aspect, the nasal dosage form is delivered to the nasalcavity of the user exposed to an organophosphate.

In another aspect, the nasal dosage form is delivered to the nasalcavity of the user before the exposure to an organophosphate.

In yet another aspect, the nasal dosage form is delivered to the nasalcavity of the user after the exposure to an organophosphate.

In yet another aspect, exposure to the oxime increases oxime exposure tothe CNS. In yet further aspects, at least 53% of the oxime is directlytransported (DTP) to the brain.

The invention will best be understood by reference to the followingdetailed description of various embodiments, taken in conjunction withthe accompanying drawings. The discussion below is descriptive,illustrative and exemplary and is not to be taken as limiting the scopedefined by any appended claims.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a schematic drawing of one embodiment of the invention.

FIG. 2 shows an embodiment of the invention.

FIG. 3 shows an embodiment of the invention.

FIG. 4 shows another embodiment of the invention.

FIG. 5 shows another embodiment of the invention.

FIG. 6 shows another embodiment of the invention.

FIG. 7 shows another embodiment of the invention.

FIG. 8 shows another embodiment of the invention with a nasal guideattached.

FIG. 9 shows an embodiment of a diffuser and compound chamber, wherebythe diffuser is cylindrical and homogeneously porous.

FIG. 10 shows an embodiment of a diffuser and compound chamber, wherebythe diffuser is cylindrical and homogeneously porous with a non-porousopen tipped cone extending into the drug product.

FIG. 11 shows an embodiment of a diffuser and compound chamber, wherebythe diffuser is cylindrical with an open tipped cone extending into thedrug product and is homogeneously porous.

FIG. 12 shows an embodiment of a diffuser and compound chamber, wherebythe diffuser is cylindrical with many open tipped cones extending fromit which allow gaseous propellant to enter the compound chamber.

FIG. 13 shows an embodiment of a diffuser and compound chamber, wherebythe diffuser is cylindrical with many cones extending from it whichallow gaseous propellant to enter the drug chamber. It also includes atube which allows propellant to enter the compound chamber ahead of thedrug to assist in aerosolization.

FIG. 14 shows an embodiment of a diffuser and compound chamber, wherebythe diffuser is cylindrical and homogeneously porous. It also includes atube which allows propellant to enter the compound chamber ahead of thedrug to assist in aerosolization.

FIG. 15 shows an embodiment of the invention where the propellant iscreated by manual air compression.

FIG. 16A shows an embodiment of the device which has a compound chamberwithin the device body which allows for propellant flow through andaround the compound chamber. FIG. 16 B shows a cross section of thedevice of FIG. 16A.

FIG. 17 shows a schematic drawing of the device used to administer 2-PAMdrug to rats in Example 1.

FIG. 18 demonstrates deposition testing of the POD device in the ratnasal cavity of 2-PAM (dark shading) being deposited on the olfactoryregion (light circle). Little drug was deposited on either therespiratory region of the nasal cavity and none was found in the tracheaor esophagus.

FIG. 19 is a graph demonstrating POD administration of a 2.5 mg dose of2-PAM that resulted in significantly lower plasma values at every pointin the first 60 minutes and overall lower plasma AUC. *=p<0.05

FIG. 20 is a graph demonstrating POD administration of a 2.5 mg dose of2-PAM that resulted in significantly higher brain values at 5 and 120minutes and an overall higher brain AUC. *=p<0.05

FIG. 21 shows the human nasal cavity model which was used m thedeposition testing of the model drug fluorescein described in Example 3.

FIG. 22 shows a processed image of human nasal cavity deposition asdescribed in Example 3. Five separate parts, vestibule 2200, turbinates2202, olfactory 2204, base 2206, and esophagus 2208, were analyzed fordeposition after a spray of the device. FIG. 22 shows a majority of thespray to be in the olfactory region.

FIG. 23 is a schematic showing the experimental setup for the impactiontesting described in Example 4.

FIG. 24 is a schematic of the experimental setup for estimating anytemperature changes on a surface that the device is targeting, which isdescribed in Example 5. A laser thermometer was used to measure thesurface temperature of a target. The device sprayed either only HFA gasor HFA gas mixed with a liquid dose and any temperature fluctuationswere noted.

DETAILED DESCRIPTION OF THE EMBODIMENTS

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art pertinent to the methods and compositions described. As usedherein, the following terms and phrases have the meanings ascribed tothem unless specified otherwise:

As used herein the specification, “a” or “an” may mean one or more.

A “diagnostic agent” refers to and encompasses an atom, molecule, orcompound that is useful in diagnosing a disease. Diagnostic agentsinclude, but are not limited to, radioisotopes, dyes, contrast agents,fluorescent compounds or molecules and enhancing agents (e.g.,paramagnetic ions). A non-radioactive diagnostic agent is a contrastagent suitable for magnetic resonance imaging, computed tomography orultrasound. The diagnostic agent can be used to perform positronemission tomography (PET), MRI, X-ray, CT, ultrasound, operative,intravascular, laparoscopic, or endoscopic procedure.

A “diffuser” refers to and encompasses a device for dispersing ordeflecting a compound in various directions.

A “frit” shall refer to and encompass a porous member or filter.

An “imaging agent” refers to and encompasses an atom, molecule orcompound that is useful in detecting physical changes or produces imagesof internal body tissues. In some aspects, the imaging agent may be adiagnostic agent.

A “propellant” shall refer to and encompass a compound that acts as avehicle for creating propulsion or thrust.

The term “therapeutically effective amount” refers to and encompasses anamount of a drug effective to treat a disease or disorder in a mammal.In one aspect, the therapeutically effective amount refers to a targetCNS concentration that has been shown to be effective in, for example,slowing disease progression. Efficacy can be measured in conventionalways, depending on the condition to be treated.

The term “treatment” and “treat”, and the like, refers to andencompasses therapeutic or suppressive measures for a disease ordisorder leading to any clinically desirable or beneficial effect,including, but not limited to, alleviation or relief of one or moresymptoms, regression, slowing or cessation of progression of the diseaseor disorder. Treatment can be evidenced as a decrease in the severity ofa symptom, the number of symptoms, or frequency of relapse.

A “user” or “subject” shall refer to and encompass a human or otheranimal. For example, the animal may be a primate or a non primate andmay include a rabbit, bovine, equine, pig, rat, mouse, dog or cat.

The device may be used in treatment, prevention, palliative care forhumans and veterinary purposes. The device may be used in research andindustrial uses. For example, the device may be used to deposit compoundin agricultural settings.

When trade names are used herein, applicants intend to independentlyinclude the trade name product formulation, the generic drug, and theactive pharmaceutical ingredient(s) of the trade name product.

For clarity of disclosure, and not by way of limitation, the detaileddescription of the invention is divided into the subsections whichfollow.

Intranasal administration of compounds offers several advantages overtraditional surgical, intravenous or oral routes for administrationacross the blood brain barrier (BBB). Intranasal administration to theolfactory region avoids gastrointestinal destruction and hepatic firstpass metabolism, such as destruction of drugs by liver enzymes, allowingmore drug to be cost-effectively, rapidly, and predictably bioavailablethan if it were administered orally. Intranasal administration providesease, convenience and safety. Intranasal drug administration isgenerally painless (taking into consideration that pain may be asubjective measurement which varies by patient) and does not requiresterile technique, intravenous catheters or other invasive devices, andis generally immediately and readily available for all patients.Intranasal administration can rapidly achieve therapeutic brain andspinal cord drug concentrations.

Nasally administered compounds contact the upper olfactory region andmolecular transport occurs directly across this tissue and intocompartments of the central nervous system. (Henry, R. J., et al.,Pediatr Dent, 1998. 20(5): p. 321-6; Sakane, T., et al., J PharmPharmacol, 1991. 43(6): p. 449-51; Banks, W. A., et al., J Pharmacol ExpTher, 2004. 309(2): p. 469-75; Westin, et al., Pharm Res, 2006. 23(3):p. 565-72). The olfactory mucosa is located in the upper nasal cavity,just below the cribriform plate of the skull. It contains olfactorycells which traverse the cribriform plate and extend up into the cranialcavity. When compounds come in contact with this specialized mucosa,they are rapidly transported directly into the brain, they bypass theBBB, and are rapidly transported directly into the central nervoussystem, often faster than if the compound is given intravenously.

The olfactory mucosa includes the olfactory epithelium. The olfactoryepithelium is located at the top of the nose between the superiorturbinate and the roof of the nasal cavity, just beneath the cribriformplate of the ethmoid bone. In humans, it covers about 10 to about 20cm2, or about 8% of the total nasal surface area, and is composed offour main cell types: epithelial cells, olfactory receptor neurons,supporting cells, and basal cells. (Mathison S. et al., (1998) Journalof Drug Targeting 5: 415-441). Although 3% of the nasal cavity isoccupied by olfactory epithelium (Morrison and Costanzo, 1990), thisroute is direct, since the olfactory neurons do not have a synapsebetween the receptive element and the afferent path (Ding and Dahl,2003). The olfactory epithelium is more than twice the depth of therespiratory epithelium, with the olfactory nerve cell bodies typicallylocated in the middle and deeper regions of the epithelium while nucleiof the supporting cells are organized in a single layer closer to themucosal surface. Tight junctions exist between the supporting cells andbetween the supporting cells and olfactory nerve cells. Morrison E. E,et al. (1992) Journal of Comparative Neurology 297(1): 1-13.

When a nasal drug formulation is delivered deep and high enough into thenasal cavity, the olfactory mucosa is reached and drug transport intothe brain and/or CSF via the olfactory receptor neurons occurs. Thetransfer of compounds from the nose to the brain is referred to as thenose-brain pathway. The nose-brain pathway has implications whencentrally acting medications such as but not limited to sedatives,anti-seizure drugs and opiates are delivered nasally. The present deviceallows for delivery via the nose-brain pathway allowing for nearlyimmediate delivery of nasal medications to the central nervous systemand brain, bypassing the blood brain barrier.

The current challenge in nose-to-brain drug delivery is also due to thecomplex architecture of the nose, which is naturally designed to channeldrugs into the lower nasal airway toward the lungs making it difficultfor drugs to reach the olfactory region. Most of the drug dispensed fromtraditional nasal devices such as sprayers or pumps is subjected to thenatural air movement in the nasal cavity towards the esophagus. Themajority of the spray dispensed from traditional devices encounters thenatural downward airflow displacement within the nasal cavity. Theremaining fraction from traditional devices is found in the respiratoryepithelium and cleared by the mucocilliary clearance mechanism orabsorbed into the blood stream. While nasal catheter instillation andnose drops are less impacted by this natural downward air movement, itrequires subjects to be in a supine position, is often associated withuser discomfort, and is not optimal for frequent clinicaladministration.

Moreover, a reservoir of residual air exists at the top of the nasalcavity that is not removed during normal respiration; thus remaining inthe olfactory region and acting as a barrier to deposition. Thisresidual air must be displaced in order to deliver aerosolized drug tothe olfactory epithelium in the upper nasal cavity in a consistentmanner. The device described herein delivers a majority of theaerosolized drug to the upper part of the nasal cavity to increaseexposure of the drug at the olfactory epithelium, a site ofnose-to-brain pathway, by both avoiding the natural downward airmovement and displacing the residual air of the upper nasal cavity.

The device herein advantageously and consistently deposits a largefraction of dose into the more distal parts of the nasal cavity such asthe olfactory region. A drug product (also referred to herein as drugformulation or nasal dosage form) is propelled from the device with avelocity into the nasal cavity.

FIG. 1 shows one embodiment of the device where a container 10 containsa propellant. The propellant may be pressurized. The propellant is afluid, for example, a liquid or gas. In one aspect, the propellant is aliquid. In another aspect, the propellant is a gas. Propellants includepharmaceutically suitable propellants. Some examples of pharmaceuticallysuitable propellants include hydrofluoroalkane (HFA) including but notlimited to HFA, HFA 227, HFA 134a, HFA-FP, FIFA-BP and the like HFA's.In one aspect, the propellant is liquid HFA In another aspect, thepropellant is gaseous HFA. Additional examples of suitable propellantsinclude nitrogen or choloroflourocarbons (CFC). Additionally,propellants may be pressurized air (e.g. ambient air). The container 10may be a conventional metered dose inhaler (MDI) device that includes apressurized canister, metering valve (including stem) to meter thepropellant upon actuation. In certain aspects, the propellant is notmetered upon actuation. In one aspect, the container 10 does not containdrug. In another aspect, the container includes a propellant and a drug.

The container 10 is in communication with a diffuser 12. For example,when the diffuser 12 is in communication with the container 10,“communication” shall refer to and encompass congruousness or fluidcommunication. The propellant from the container 10 is diffused via thediffuser 12. In one aspect, a majority of the propellant is diffused viathe diffuser 12. In another aspect, a minority of the propellant isdiffused via the diffuser 12. Majority refers to and encompasses atleast 50 percent. Minority refers to and encompasses less than 50percent. In another aspect, at least about 10%, 15%, 20%, 25%, 30%, 35%,40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or about100%, inclusive of endpoints, of the propellant is diffused via thediffuser 12. The diffuser 12 is in communication with the compoundchamber 14. The compound chamber 14 is capable of holding a compound,such as but not limited to a drug or/and a diagnostic agent. In oneaspect, the diagnostic agent is an imaging agent. In an example, theimaging agent is fluorodeoxyglucose (FDG) or fluorothymidine (FLT). Inanother aspect, the compound is a drug. In another aspect, the compoundis not an imaging agent. In one aspect, the compound is a liquid. Inanother aspect, the compound is a powder. In yet another aspect, thecompound is an intranasal formulation of a drug in a liquid or powderedstate. The intranasal formulation may contain suitable intranasalcarriers and excipients known in the art.

The propellant in the container 10 acts as a vehicle to deliverpropulsion or thrust to expel from the compound chamber 14 the compound.The compound chamber 14 is in communication with a nozzle 16. Thepropulsion or thrust from the propellant is capable of expelling thecompound from the compound chamber 14 and nozzle 16 when incommunication with the compound chamber 14.

In one aspect, when the MDI device is actuated, a discrete amount ofpressurized HFA fluid is released. The MDI may contain between about 30to about 300 actuations, inclusive of endpoints, of HFA propellant. Theamount of fluid propellant released upon actuation may be between about20 and about 200 μl, inclusive of endpoints, of liquid propellant.

FIG. 2 shows one embodiment of the device. The actuator body 20 houses acontainer 10, in one aspect the container 10 is a metered dose inhalerthat includes a propellant canister 18 having a neck 19 and a meteringvalve assembly 21. A valve stem 23 is in communication with a connectionchannel 22. The propellant exiting the valve stem 23 is a fluid. Thefluid may be liquid, gas, or a combination. A diffuser 28 is incommunication with the propellant exiting the container 10 and thecompound chamber 14.

Propellant exiting the container 10 comes into contact with the diffuser28. The diffuser 28 is capable of converting liquid propellant exitingthe container 10 into gaseous propellant. In one aspect, the diffuser 28is capable of converting all or a majority of the liquid propellant intogaseous propellant. In another aspect, the diffuser is capable ofconverting a minority of the liquid propellant into gaseous propellant.Majority refers to and encompasses at least 50 percent.

Minority refers to and encompasses less than 50 percent. In anotheraspect, at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%,60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or about 100%, inclusive ofendpoints, of the liquid propellant is converted into gaseouspropellant. Following contact with the diffuser 28, the diffusedpropellant comes into contact with the compound in the compound chamber14. The diffused propellant and the compound come into contact with eachother as the propellant propels the compound in the compound chamber 14.The nozzle 16 is in fluid communication with the compound chamber 14.The compound is propelled by the diffused propellant into communicationwith the nozzle 16. The propellant propels the compound to be expelledvia the distal end of the nozzle 16. Exiting from the nozzle 16 iscompound, propellant, or a combination thereof.

In some aspects, the diffuser 28 functions to convert propellant from aliquid to a gas. In other aspects, the diffuser 28 functions to preventthe compound contained in the compound chamber 14 from coming in contactwith the container 10. In another aspect, the diffuser acts as a one waycheck valve. In other aspects, the diffuser 28 functions to convertpropellant from a liquid to a gas and to prevent the compound containedin the compound chamber 14 from coming into contact with the container10. In yet another aspect, the diffuser functions to increase thetemperature of the propellant.

An example of a diffuser 28 includes a frit, a plurality of frits, or adiffuser member or combinations thereof. In one aspect, the diffuser isa frit. In another aspect, the diffuser is a plurality of frits. Inanother aspect, the diffuser is a diffuser member.

In one aspect, the frit(s) are of any suitable size and shape and areformed using any suitable porous material of any suitable density. Inone aspect, the frit is made of a hydrophobic material. In one aspect,the frit is made of an inert material to avoid chemically reacting withany of the compounds. The inert material may be metal or non metal. Inone aspect, the frit is composed of metal. In another aspect, the fritis composed of a non-metal. In one aspect, the inert material issintered nickel. As one example, a frit formed using a porous stainlesssteel having a pore size in the range of approximately 1 micron toapproximately 100 microns can be used. In another aspect the pore sizesis in the range of about 1 to about 10, about 10 to about 20, about 20to about 30, about 30 to about 40, about 40 to about 50, about 50 toabout 60, about 60 to about 70, about 70 to about 80, about 80 to about90, about 90 to about 100 microns, inclusive of endpoints. In anotheraspect, the frit can be formed using aluminum foam. The number and sizeof the pores and the overall dimensions (e.g., diameter and thickness)of the frit are set to maximize surface area for vaporization whilelimiting pressure drops accompanying passage of vaporized propellantthrough the frit. In certain aspects, the frit may be constructed ofTeflon, glass, metal mesh, screen, porous metal, polyether ether ketoneor another plastic material. In one aspect, the passage of liquidpropellant through the increased surface area of the frit transitionsthe liquid to gas and increases the temperature of the resulting gas. Inanother aspect, the passage of gas propellant through the increasedsurface area of the frit increases the temperature of the gas.

As shown in FIG. 2 , in one aspect, the diffuser 28 is disposed on theconnection channel 22. In another aspect, the diffuser 28 is disposedwithin a drug chamber 24 whereby an intranasal dosage form is disposedin the drug chamber 24. A nozzle 26 is in communication with the drugchamber 24. The diffuser 28, drug chamber 24 and nozzle 26 are housed bya drug capsule body 30 adjacent the actuator body 20.

The drug capsule body 30 may be of any suitable material to house thecomponents. In one aspect, the drug capsule body 30 may be constructedfrom plastic. In one aspect, the drug capsule body 30 may taper at thedistal end to allow the nozzle 26 to be brought closer to the septum.The taper functions to improve the positioning of the device at asuitable horizontal angle relative to the upper nasal cavity.

Shown in FIG. 3 is another embodiment of the device. The actuator body32 (or, housing) houses the propellant canister 34 having a neck 33 anda metering valve assembly 35. A valve stem 37 is disposed within aconnection channel 36. The propellant exiting the valve stem 37 is in aliquid form or a mixture of liquid and gaseous form. A diffuser 44 isdisposed on the channel 36 and is adapted to convert a majority or allof the liquid propellant into gaseous propellant. The diffuser 44 isdisposed within a drug chamber 42, whereby the intranasal dosage form isdisposed in the drug chamber 42. A nozzle 40 is in communication withthe drug chamber 42. The diffuser 44, drug chamber 42 and nozzle 40 aredisposed within a drug capsule 46 adjacent the actuator body 32.

An insertion port 38 is provided for the insertion of a compound intothe drug chamber 42. The insertion port 38 may be constructed fromsilicone or plastic. In one aspect, the needle of a syringe may beinserted through the insertion port 38 so as to inject the compound intothe drug chamber 42. In one aspect, the compound is a drug. In anotheraspect, the compound is a diagnostic agent. In yet another aspect, thecompound is not an imaging agent. The drug may be a liquid or a powder.

Shown in FIG. 4 is another embodiment of the device. A housing body 48houses a pressurized propellant container 50, a connection channel 52, arelease valve assembly 51, a diffuser 54, a drug chamber 56 and a nozzle58. The pressurized propellant container 50 contains a liquid propellantand has a release valve assembly 51. A connection channel 52 iscongruous with the release valve assembly 51 of the container 50 and adiffuser 54. The diffuser 54 is in communication with a drug chamber 56.In one aspect, the drug chamber contains a drug-containing intranasaldosage form. A nozzle 58 is in communication with the drug chamber 56.

Shown in FIG. 5 is another embodiment of the device. An actuator body 60houses a propellant container 62 having a neck 61, a metering valveassembly 63 and valve stem 65. A valve stem 65 is disposed within aconnection channel 72. The propellant exiting the valve stem 65 is in aliquid form, gaseous form, or a mixture of liquid and gaseous form. Adiffuser 70 is disposed on the channel 72 and is adapted to convert theliquid propellant into gaseous propellant. The diffuser 70 is mcommunication within a drug chamber 68. In one aspect, the drug chamber68 contains an intranasal dosage form. A nozzle 66 is in communicationwith the drug chamber 68. The diffuser 70, drug chamber 68 and nozzle 66are disposed within a drug capsule 69 adjacent to the actuator body 60.The actuator body 60 is shaped allowing or accommodating for an aimingguide. The aiming guide includes one, a plurality, or all of thenose-aiming guide 64, the septum-aiming guide 74, an upper lip aimingguide 76, and a visual indicator 71.

In one aspect, a nose-aiming guide 64 is provided on the actuator body60. The nose-aiming guide 64 functions to accommodate the user's nose.In another aspect, the nose-aiming guide 64 functions to aim the nozzle66 at the user's olfactory region.

In another aspect, a septum-aiming guide 74 is provided on the actuatorbody 60. In one aspect, the septum-aiming guide 74 functions toaccommodate contacting the user's septum.

In yet another aspect, an upper lip aiming guide 76 is provided on theactuator body 60. The upper lip aiming guide 76 functions to accommodatecontacting the user's upper lip. In one aspect, a visual indicator 71 isprovided to alert the user to the length or amount of the capsule's 70insertion into the user's nasal cavity. In one aspect, the visualindicator 71 is inserted to a specified amount or length into the user'snasal cavity.

Shown in FIG. 6 is another embodiment of the device. A housing body 80houses a pressurized propellant container 94, a release valve assembly,and a connection channel 92. The pressurized propellant container 94contains the liquid propellant and has a release valve assembly. Aconnection channel 92 is in communication with the release valveassembly and a diffuser 84. The diffuser 84 is in communication with thedrug chamber 82. In one aspect, the drug chamber 82 contains anintranasal dosage. A nozzle 78 is in communication with the drug chamber82.

In one aspect, a guide function is provided. The guide function includesa guide post 86. The guide post 86 is adjacent to a guide post arm 88.The guide post arm 88 is integral to a rotation arm 90. The rotation arm90 may be affixed or rotatably connected to the housing body 80 so as toaccommodate right or left-handed users. The guide post 86 guides aimingof the nozzle 78 within the user's nasal cavity by entering the opposingnaris of the user and by limiting the angle of administration. In oneaspect, the guide post arm 88 and rotation arm 90 is constructed ofplastic. In yet another aspect, the guide post arm and rotation arm isconstructed of structural foam.

Shown in FIG. 7 is another embodiment of the device. A housing body 98is provided to assist in placement and to house the various componentstructures shown. A pressurized propellant container 108 containspropellant and has a release valve assembly. A connection channel 104 isdisposed between the release valve assembly and a diffuser 102. Thediffuser 102 is disposed within a drug chamber 100, whereby thedrug-containing intranasal dosage form is disposed within the chamber100. A nozzle 96 is disposed on the chamber 100.

Shown in FIG. 8 is a nasal guide 112 which could be added to the drugchamber 118. The guide would not obstruct the nozzle 116 or the nozzleorifices 114 and would serve to limit the placement/insertion of thedevice within the nasal cavity to the desired angle of administration.

FIG. 9 shows one embodiment of a diffuser 122 and its relationship withthe drug chamber 130. Propellant comes into contact with the diffuser122. The diffuser 122 converts the liquid propellant to gaseouspropellant. In one aspect, it converts a majority of the liquidpropellant into a gaseous propellant. In another aspect, it converts aminority of the liquid propellant into a gaseous propellant. In yetanother aspect, it converts all of the liquid propellant into a gaseouspropellant. In one aspect, the diffuser 122 is cylindrical in shape. Inyet another aspect, the diffuser 122 is congruous in shape with the drugchamber 130.

The diffuser 122 is porous. The pores may be homogenous in size andshape. In another aspect, the pores of the diffuser 122 areheterogeneous in size and shape. In yet a further aspect, the diffuser122 is homogenously porous. In yet a further aspect, the diffuser 122 isheterogeneously porous. As shown in FIG. 9 , the diffuser 122 iscylindrical in shape and is homogenously porous, whereby the gas maypass through the pores, but the pores are impervious to the drug product124. The gaseous propellant then contacts a drug product 124 propellingthe drug product 124 through a nozzle 128 and out of the device.

FIG. 10 shows is another embodiment of the diffuser 134 and itsrelationship with the drug chamber 138. A propellant comes into contactwith the diffuser 134, propelling the drug product 142 through a nozzle146. A portion of the gaseous propellant exiting the diffuser 134 ispropelled through a diffuser extension 140, which aids in aerosolizationof the drug product 142. As shown in FIG. 10 , the diffuser 134 isheterogeneously porous via the diffuser extension 140.

FIG. 11 shows another embodiment of the diffuser 150 and itsrelationship with the drug chamber 154. Propellant comes into contactwith the diffuser 150. The diffuser 150 is an extended shape orelongated shape. In one aspect, the diffuser 150 is an extendedcylindrical shape. The function of the extended cylindrical shape is toincrease the area of diffuser 150 in the drug chamber 154 and contactwith any drug product 156 contained therein. A portion of the gaseouspropellant contacts drug product 156 propelling the drug product 156into a nozzle 160. Another portion of the gaseous propellant passesthrough the extended or elongated shape, aiding in aerosolization of thedrug product 156. As shown in FIG. 11 , the diffuser 150 is cylindricalin shape and is homogenously porous, whereby the gas may pass throughthe pores, but the pores are impervious to the drug product 156.

FIG. 12 shows another embodiment of the diffuser 164 and itsrelationship with the drug chamber 166. The propellant contacts thediffuser 164. The diffuser 164 has a plurality of conical points eachwith a distal hole at the tip, whereby the tips permit flow primarily ofthe gaseous propellant in the drug product 168. The propellant contactsthe drug product 168 propelling it through the nozzle 172.

FIG. 13 shows another embodiment of the diffuser and its relationshipwith the drug chamber 178. The propellant contacts the diffuser member176. The diffuser member 176 has a plurality of conical points each witha distal hole at the tip, whereby the tips permit flow of the primarilygaseous propellant in the drug product 180. A diffusion tube 182 allowspropellant mixture to bypass the drug product 180 into the void space184. The gaseous propellant exiting the diffuser member 176 contacts thedrug product 180 propelling it into the void space 184 and through anozzle 186.

The diffusion tube 182 allows for respiration to occur concurrent withuse of the device. As a user uses the device, the diffusion tube 182allows for inhalation by the user to bypass inhalation of the drugproduct 180 contained in the drug chamber 178. Further, the diffusiontube 182 allows for propellant to aerosolize the drug product 180 as itcomes into contact with the drug product 180 in the drug chamber 178.The drug product 180 exits the device aerosolized. In another aspectabsent the diffusion tube 182, the drug product 180 exits the nozzle asa liquid or partial aerosol or a combination. In one aspect, a frit or aplurality of frits (not shown) is in communication with the diffusiontube 182 and/or diffuser member 176 so as to act as a check valve

FIG. 14 shows another embodiment of the diffuser 190 and itsrelationship with the drug chamber 194. The propellant contacts thediffuser 190 that is homogenously porous whereby the gas may passthrough the pores, but the pores are impervious to the drug product. Adiffusion tube 196 allows propellant mixture to bypass the drug product192 into the void space 197. The gaseous propellant exiting the diffuser190 contacts the drug product 192 propelling it into the void space 197and through a nozzle 198.

The diffusion tube 196 allows for respiration to occur concurrent withuse of the device. As a user uses the device, the diffusion tube 196allows for inhalation by the user to bypass inhalation of the drugproduct 192 contained in the drug chamber 194. Further, the diffusiontube 196 allows for propellant to aerosolize the drug product 192 as itcomes into contact with the drug product 192 in the drug chamber 194.The drug product 192 exits the device aerosolized. In another aspectabsent the diffusion tube 196, the drug product 192 exits the nozzle 198as a liquid or partial aerosol or a combination. In one aspect, a fritor a plurality of frits (not shown) is in communication with thediffusion tube 196 so as to act as a check valve.

FIG. 15 shows another embodiment of the device. The manual pressureactuator allows the user to administer the device without the need of aprefilled pressurized canister or HFA canister. This device has a piston200 which is depressed into the air compression chamber 202 resulting ina quantity of compressed air held within the air compression chamber202. The trapped air is thus raised from ambient pressure to severaltimes that of ambient air pressure. In one aspect, the manual pressureactuator is a syringe or syrette. The device contains a lock pin 204that is inserted to hold the piston in the high pressure position. Inaddition the device contains a trigger valve 206. In an aspect, thetrigger valve 206 is similar to a stopcock valve. There is a diffuser208 in communication with the trigger valve 206 and the compound holdingchamber 210. The compound is placed in the compound holding chamber 210which is in communication with a nozzle 212. While the device is put inthe high pressure state, the trigger valve 206 is placed in the loadposition, which blocks the high pressure air in the air compressionchamber 202. When the trigger valve 206 is moved into the open positionby the user, the compressed air in the air compression chamber 202travels through the diffuser and into the compound holding chamber whereit mixes with the compound. A mixture of compressed air and compoundthen exits the device through the nozzle 212 with a positive velocity.

FIG. 16A shows another embodiment of the device which is suitable todeliver a compound into the nasal cavity of an animal or human. Apressurized propellant container 214 is in communication with a diffuser216. The diffuser 216 is in communication with the interior of thehousing body 218 and with the compound chamber 220. The interior of thehousing body 218 is in communication with a nozzle 222. FIG. 16B is across section of FIG. 16A at the dashed line. FIG. 16B shows that thecompound chamber 220 is connected to the housing body 218 by flanges224. The propellant is diffused by the diffuser 216 and the flanges 224allow the diffused propellant to travel both through the compoundchamber 220 and also around the compound chamber 220. When thepressurized propellant container 214 is actuated to release an amount ofpropellant, the propellant travels through the diffuser 216. Thediffuser disperses the propellant into the interior of the housing body218 and into the compound chamber 220 where the propellant mixes withthe compound. The propellant also travels on the outside of the compoundchamber 220 and then mixes with the compound exiting the compoundchamber 220. The mixture of pharmaceutical compound and propellant thenexits the nozzle 222. As a user uses the device, the relationship of thecompound chamber 220 with the housing 218 allows for inhalation by theuser to bypass inhalation of the drug product contained in the compoundchamber 220.

The device may be for pediatric or adult use. One of skill in the artcan envision modifications of the device to accommodate for pediatric oradult use.

In another embodiment, the device delivers a compound through the mucosaor epithelium of the tongue, mouth, skin, or conjunctiva. In anotherembodiment, the method includes administering a composition of thecompound on or to the tongue, on or to the skin, or on or to theconjunctiva of the subject.

In yet another embodiment, the device delivers the compound to theturbinate regions of the nasal cavity. In one aspect, the devicedelivers the compound primarily to the turbinate regions of the nasalcavity.

In additional embodiments, the device may be used for treatment,prevention, or palliative care. The device may be used in research orindustrial purposes. The device can be used to disperse a compound whichhas been propelled by a propellant having been in communication with adiffuser. For example, the device may be used in agriculture to dispensean agricultural compound.

An intranasal formulation of an oxime is provided. Additionally, amethod of intranasal administration of an oxime to the olfactory regionis described.

Oximes can be delivered to the central nervous system (CNS) for theprevention, treatment, and palliative care of exposure toorganophosphate (OP) compounds such as chemical warfare nerve agents(e.g. sarin, tabun, soman, Russian VX, etc.) or pesticides (e.g.diisopropylfluorophosphate). Oximes had traditionally been delivered,for example, intravenously. Intranasal administration of an oxime to theolfactory region allows for transport across the BBB.

Nerve agents containing organophosphorous compounds are a significantthreat to the warfighter, who may be exposed in battlefield settings onland, sea, air and space. Civilian populations also face health risksassociated with nerve agents during the use of commercially availablepesticides, as do first responders to a terrorist attack. The currenttreatment regimen for nerve agent exposure includes the use of acholinergic reactivator (pralidoxime, 2-PAM), muscarinic receptorantagonist (atropine) and an anticonvulsant (diazepam). While 2-PAM andatropine are available in multiple injection formats, (e.g. IV infusionor IM autoinjector), injection presents significant and practicalchallenges in the battlefields, such as the need to remove body armor,and have correct training in the use of autoinjectors. Moreover, neweroximes such as MMB4 and HI6 are difficult to formulate in currentautoinjector formats. There is great need to develop practical, moreeffective and rapid onset systems capable of distributing anti nerve gasagents, such as oximes, capable of penetrating into the central nervoussystem (CNS) of subjects in battlefield and emergency situations.

The method for delivering an oxime across the blood brain barrier to asubject in need thereof includes administering to the subject atherapeutically effective dosage of an oxime, where the dosage isdelivered to the upper olfactory region of the nasal cavity.

In one aspect of the method, the therapeutically effective amount of anoxime administered to the user is within the range of about 0.001 mg/kgto about 100 mg/kg.

In another aspect of the method, the therapeutically effective amount ofan oxime administered to the user is within the range of about 0.01mg/kg to about 10 mg/kg.

In yet another aspect of the method, the therapeutically effectiveamount of an oxime administered to the user is within the range of about0.1 mg/kg to about 1 mg/kg. In one aspect, the mg/kg is mg of compoundper kilogram of body weight. In another aspect, the dosage is a flatdosage independent of weight.

In performance of the method of delivery of an oxime intranasally to theolfactory region includes providing the device described herein forinsertion into the user's nasal cavity. The device is inserted into theuser's nasal cavity. At least one therapeutically effective dose of anoxime is delivered via the device. At least one therapeuticallyeffective dose of the oxime is delivered to the olfactory region.Delivery of the oxime to the olfactory region allows for delivery of theoxime across the BBB.

Oximes such as but not limited to 2-PAM (2-pyridine aldoxime methylchloride), MMB4, HI6, TMB4, Hlo7 are currently used to treat OP exposurebut they poorly penetrate the blood-brain-barrier. Thus, the oximes, intheir current form of administration, do little to treat or prevent theCNS damage caused by these compounds.

By using the using the device described herein for the method, thecompound, such as the oxime, can be self-administered, or administeredby a battle-buddy or civilian, with or a user without prior medicaltraining. The device delivers compound without requiring a specificbreathing pattern by the user and can be administered to an unconscioususer.

Direct transport percentage (DTP %) to the brain was calculated using anoxime to determine the amount of drug in the brain that was distributeddirectly from the nasal cavity to the CNS. In one embodiment, the DTPwas 62.6+/−9.6%. In one aspect, the DTP was greater than 64.2%. Inanother aspect, the DTP was at least 64.3%. In another aspect, the DTPwas at least 53%. In another aspect, the DTP was greater than 53%. Inanother aspect, the DTP was greater than 55%. In another aspect the DTPwas at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or100%, inclusive of endpoints. In another aspect, the DTP was at leastabout 40%, 45%, 505, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or100%, inclusive of endpoints.

The device deposits a compound on the olfactory region. In oneembodiment, the percent deposition of the compound is at least 64.2%. Inone aspect, the percent deposition of the compound was greater than64.2%. In another aspect, the percent deposition of the compound was atleast 64.3%. In another aspect, the percent deposition of the compoundwas greater than 50%. In another aspect, the percent deposition of thecompound was greater than 55%. In another aspect the percent depositionof the compound was at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 99%, or 100%, inclusive of endpoints. In another aspect, thepercent deposition of the compound was at least about 40%, 45%, 505,55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100%, inclusive ofendpoints.

Compounds which can be delivered by the device described include but arenot limited to those for the palliative, prevention or treatment ofinfectious diseases, inflammatory diseases, and oncology. Compoundswhich can be delivered by the device include but are not limited tothose for the palliative, prevention or treatment of Parkinson'sdisease, Alzheimer's disease, depression, stroke, epilepsy, autism,lysosomal storage disorders, fragile X syndrome, ataxis, insulindeficiency, and blindness. Compounds which can be delivered include butare not limited to deferoxamine (DFO), glucagon-like peptide-1antagonist, cephalexin, midazolam, morphine, insulin-like growthfactor-1, nerve growth factor, insulin, oximes, imaging agents includingbut not limited to FDL and FLT, GDP-5, and cytokines including but notlimited to interleukins (i.e., IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7,IL-8, IL-9 and IL-10), interferons, and tumor necrosis factor (i.e.,TNF-a and TNF-β).

The invention is further described in the following examples, which arein not intended to limit the scope of the invention.

EXAMPLES Example 1

An oxime drug, 2-PAM, was administered into the olfactory nasal regionin rats with the device, (e.g. a Pressurized Olfactory Delivery (POD)device). The brain and plasma concentrations of 2-PAM was measured atcertain time points after drug administration. The device enableddelivery of 2-PAM resulted in higher brain exposure and lower plasmaexposure compared to intravenous injection.

Animal use. Rats were used for deposition, tolerability and distributionexperiments. Adult male Sprague-Dawley rats (200-300 g; Harlan,Indianapolis, Ind.) were housed under a 12 hour light/dark cycle withfood and water provided ad libitum. Animals were cared for in accordancewith institutional guidelines, and all experiments were performed withan approved protocol from the Pacific Northwest Diabetes InstituteInstitutional Animal Care and Use Committee under protocol number 12610.

Statistical analysis. In most cases where two values were compared at-test was used. When more than two groups were compared, such ascomparing the powder 2-PAM POD formulation with the aqueous 2-PAM PODformulation and the IV 2-PAM, a two-way ANOVA was used with a bonferronipost test. When comparing the AUC plasma and brain values which werederived from different animals at each time point the method describedin Westin et al., 2006 was used. In all cases statistical significancewas defined asp<0.05.

Aqueous formulations of 2-PAM were made by dissolving 2-PAM in deionizedwater. 2-PAM was dissolved into 500 μl of water at 10 mg/ml, 100 mg/ml,250 mg/ml, and 500 mg/ml and left in a closed microcentrifuge tube atambient temperature (25°). These water based formulations were thenvisually observed at 1 hour, 24 hours, and 48 hours for any cloudinessor precipitant.

Dry powder formulation of 2-PAM was prepared by placing the 2-PAM freedrug in a microcentrifuge tube and grinding the drug with a motorizedpestle (Kontes, Vineland, N.J.). The 2-PAM powder was then observedunder a microscope to ensure the homogeneity of the powder formulation.The 2-PAM was ground with a pestle to ensure that there were noagglomerations of 2-PAM greater than 100 μm in diameter. Such largeragglomerates could clog the 810 μm diameter POD nozzle used in the ratexperiments.

The construction of the rat use POD nasal aerosol device is illustratedin FIG. 17 . A meter dose inhaler (MDI) can dispensing 25 μlhydrofluoroalkane 227 1700 is attached to the plastic actuator 1702. Theactuator is in gas communication with a polytetrafluoroethylene frit1704 which had a 50 μm pore size. The polytetrafluoroethylene frit 1704is in communication with the dose holding cylinder 1706 which is placedinside the body 1708 of the POD in order to create an aerosolized flow.On actuation the HFA propellant 1700 is converted to a gas by passingthrough the polytetrafluoroethylene frit 1704 and then it mixes with thedose 1706 and the dose and propellant mixture exits from the 23 gaugestainless steel tubing nozzle 1710 which is covered with a fluorinatedethylene-propylene liner that was placed over the outside of the metaltip in order to protect the nasal epithelia from being damaged by thenozzle 1710 during use. The construction of the rat use POD device wassuccessful and consistently delivered powder 2-PAM formulations with nomeasurable residual drug left in the device

The basic operation of either POD device in rats was as follows. Theanimal was anesthetized with 5% isoflurane for 2 minutes to enableconsistent administration. The rat was removed from the isofluranechamber and placed in a supine position. The dose was loaded into thedevice and the nozzle was carefully placed 8.0 mm into the rat nasalcavity and pointed in the direction of the cribriform plate. Then theMDI can was pressed to discharge the dose into the rat nasal cavity. Inaddition, the dry powder dose chamber was weighed on a scale with asensitivity of 0.1 mg (Mettler Toledo, Columbus, Ohio) before loadingthe dose, after the dose was placed in the dose loading chamber, andafter firing to ensure that the correct dose was loaded into the deviceand that the complete dose was released into the rat nasal cavity.

The 2-PAM formulations were made with 0.1% coomassie blue dye in orderto test nasal cavity deposition in rats. The animals were dosed usingthe dry power POD device as described above with a single dose of 2.5 mgdose of 2-PAM with coomassie blue. Shortly after administration wascomplete (<5 minutes), the animals were overdosed with 250 mg/kgpentobarbital. The nasal cavity was then bisected at the septum, theseptum was removed, and the tissues were examined for dye localization.In addition the trachea and esophagus were dissected from the back ofthe mouth to the lungs to determine if the POD spray deposited any 2-PAMbeyond the nasal cavity. This deposition study was performed with N=4rats. The typical result of the deposition testing is shown in FIG. 18 .In FIG. 18 the olfactory region of the rat nasal cavity in the upperpanel is circled in white. The dark dye can be seen as being depositedprimarily within this olfactory region.

A sensitive LC/MS method was established m order to determine thedistribution of POD administered 2-PAM in both the plasma and the brainof rats. A fixed volume (20 μl) of 2Chlorolmethylpyridinium iodide d6(Cerilliant, Palo Alto, Calif.) was added into each tissue and plasmasample to act as an internal standard. Tissue samples were homogenizedin 3 mls of water. 60 μl of acetonitrile was added to the samples tocause protein precipitation. The samples were centrifuged for 10 minutesat 1000 g. An Agilent HPLC/MS series 1100 series B with autosampler(Agilent, Technologies, Inc., Santa Clara, Calif.) was used forquantification. The injection volume was 5 μl. The morphine samples werepassed over a Phenomenex Synergi 4 u PolarRP00 80A (Agilent,Technologies, Inc., Santa Clara, Calif.) with a flow rate of 0.3 ml/min.

A standard curve was created on the day of analysis according to thesame process described for the samples. Each standard curve was linearwith a coefficient of linear regression R2>0.99. In addition, twoquality control samples with a known amount of drug were processed onthe day of analysis in order to ensure day to day consistency of theanalytical assay.

This LC/MS method was successful and resulted in reproduciblequantification of both tissue and brain samples. The 2-PAM detectablepeaks were much higher than background in most cases. The sensitivity ofthis detection method was 0.05 μg/ml in plasma and 1.0 ng in braintissue. This method could be used in future studies with primates or inclinical studies.

In the tissue distribution experiments, the animals were anesthetizedwith 5% isoflurane for two minutes. Then the animals were removed fromthe isoflurane induction box and placed in a supine position. Theanimals were then dosed with either the POD device (2.5 mg in a single10 μl dose) or via intravenous injection (2.5 mg in 500 μl). Animalsthat were sacrificed 5 minutes after dosing remained under 2% isofluraneanesthesia until they were sacrificed. The animals sacrificed at theremaining time points were allowed to wake up from isoflurane anesthesiaand placed back into housing. At 3 minutes before the sacrifice time theanimals were again exposed to 5% isoflurane and then quickly overdosedwith Beuthanasia-D (Schering-Plough Animal Health Corp, North Chicago,Ill.). Using IV 2-PAM and the aqueous POD formulation of 2-PAM, animalswere sacrificed at 5, 15, 30, 60, and 120 minutes (N=6). Animals dosedwith the dry powder 2-PAM POD formulation were sacrificed at 5 and 15minutes (N=6).

Immediately after death, the animal was decapitated. Blood was collectedfrom the trunk and placed in a microcentrifuge tube with 10 μl of 40 mMEDTA. The plasma was separated from the blood by centrifuging at 6,000 gfor 10 minutes. Then the plasma was frozen until it was analyzed for2-PAM concentration with the LC/MS method previously described. The baseof the skull and the parietal bones were quickly removed from the head.The brain was removed within 2 minutes of sacrifice. The brain wasplaced in a microcentrifuge tube and frozen until it was analyzed for2-PAM concentration with LC/MS.

A direct transport percentage (DTP %) to the brain was calculated inorder to determine the amount of drug in the brain that was distributeddirectly from the nasal cavity to the CNS. The DTP % is used to estimatethe amount of drug in the brain that cannot be accounted for by systemicdistribution. The DTP as defined was calculated as follows:

Administration of the aqueous formulation of 2-PAM with POD resulted inlower systemic exposure and greater CNS exposure compared to anequivalent IV dose. The IV dose resulted in a typical plasma curve withthe highest point at 5 minutes (FIG. 19 ). The POD administered 2-PAMresulted in plasma concentrations that were lower than the IV values,which is not expected given 2-PAM's limited absorption across the nasalrespiratory epithelium into the blood stream. The total plasma AUC wassignificantly lower after POD administration compared to IVadministration.

$\frac{{AUC}_{{brain}{({IV})}}}{{AUC}_{{plasma}{({IV})}}} = \frac{B_{X}}{{AUC}_{{plasma}{({nasal})}}}$${DTP}\mspace{14mu}\%\;\frac{{AUC}_{{brain}{({nasal})}} - B_{X}}{{AUC}_{{plasma}{({nasal})}}} \times 100\%$

In contrast to the plasma values, the brain concentrations of 2-PAMafter POD administration were significantly higher than after IVadministration at both 5 and 120 minutes (FIG. 20 ). In addition, thetotal brain concentration AUC was significantly greater after PODadministration compared to IV. Of interest for the application of 2-PAMas a nerve gas exposure treatment is the fact that at 5 minutes afteradministration, POD 2-PAM resulted in 3.5× the brain concentrationcompared to IV administration.

The brain-to-plasma ratios were significantly higher after POD 2-PAMcompared to IV at every time point except for 30 minutes (Table 1).These increased ratios point to the fact that a portion of the drug wasdirectly delivered to the brain from the nasal cavity, effectivelybypassing the blood brain barrier. When the direct transport percentage(% DTP) was calculated it was found to be 80.9%. This % DTP canprimarily be accounted for by the large brain values found 5 minutesafter POD 2-PAM administration. Table 2 shows brain to plasmaconcentration ratios. At each time point except for 30 minutes, PODadministration resulted in significantly Greater brain to plasma rationswith a 15.25 fold increased brain to plasma ration after 5 minutes.

Table 1 Time (min.) POD IV 5 132.7* 8.7 15 58.5* 13.1 30 41.1 16.8 6061.4* 11.7 120 126.7* 6.7

The powder formulation of 2-PAM administered via the POD device led toeven greater 2-PAM concentrations in the brain (Table 2). The powder2-PAM POD study was more limited than the aqueous formulation, but at 5and 15 minutes after administration the powder formulation resulted insimilar blood levels compared to the aqueous 2-PAM POD, butsignificantly higher brain concentrations.

TABLE 2 Plasma 2-PAM Standard concentration (ng/g tissue) deviation timepowder powder (min) POD IV POD POD IV POD  5 0.44 1.42* 0.46  5 0.1 0.40.27 15 0.33 0.73* 0.38 15 0.1 0.2 0.11 Brain 2-PAM standardconcentration (ng/g tissue) deviation time powder powder (min) POD IVPOD POD IV POD  5 41.6 11.9 106.19*  5 19.0 2.0  11.75 15 10.4  9.0293.32  15  6.4 1.0 220.27

Table 2 shows distribution of the powder formulation of 2-PAMadministered via POD. The powder formulation of POD resulted in plasmavalues at 5 and 15 minutes that were not significantly different thanthe liquid formulation of POD. However, the 2-PAM concentrations afterPOD administration of the powder formulation were significantly greaterthan either the aqueous POD 2-PAM or the IV 2-PAM. *=p<0.05

The pharmacokinetic and distribution experiments resulted in datasupporting the potential of POD administered 2-PAM as a treatment fornerve gas exposure. The POD administration in both the aqueousformulation and the powder formulation resulted in high brain exposurewithin the first 5 minutes of administration.

Example 2

The device used in Example 2 is described in FIG. 3 . The device in thisexample is referred to as a pressurized olfactory delivery (POD) device.In order to determine the amount of compound being delivered from thedevice to the olfactory region of the nasal cavity a method wasdeveloped for determining the percentage of dose deposited within keyregions of a human nasal cavity model. This method relies on aquantitation by image analysis and is able to detect and quantitatedeposition within 5 specified regions that describe the whole nasalmodel, including the upper olfactory region.

Materials: A human nasal cavity model was constructed from clear heatmoldable plastic sheeting. (FIG. 21 ) This mold is thin-walled and istransparent to a blue light source that allows for the excitation of theindicator dye fluorescein used in the experimental doses. This humannasal cavity model was based on a computer model generated from MRIscans from multiple subjects (Liu, J Appl Physiol, 2009 March;106(3):784-95). The model therefore represents an “average” human nasalcavity.

A stage for positioning the nasal models and aiming the POD deviceduring targeting and actuation was designed and constructed. This stagewas flexible enough in operation to allow for a wide set of aimingangles, both horizontal and vertical. By aiming the device at variousangles with respect to the nasal cavity, the robustness of the deviceadministration could be tested.

A thin walled transparent nasal model was prepared by coating the insidewith a very thin layer of imitation mucus, which was simply a storebought hand sanitizer solution. The prepared model was then photographedin a custom made transilluminator/photo box as a blank reference forthat particular experimental point. The model was then mounted onto thestage along with the POD device that has been loaded with a dose of 0.1mg/mL Fluorescein/water. Immediately after POD actuation, the model wasremoved from the stage and held horizontally to prevent dose migrating.As soon as possible, the dosed model was placed in thetransilluminator/photo box and photographed. The model was then washedunder a stream of tap water and dried by shaking or forced air to bereadied for another test. The two camera images were then digitallyanalyzed as described below to reveal deposition within the model.

Data processing of the blank and experimental images obtained wascarried out with ImageJ software. For ImageJ to repeatedly compareimages and perform background subtraction accurately, the digitalphotographs were taken with the model carefully held in the sameregister within the transilluminator/photo box. ImageJ performs threekey functions: 1) the image was color processed with the RGB channelsplitter. This function eliminates red and blue signals from the image,leaving primarily signal generated by the fluorescent signal from thefluorescein in the dose.

The ImageJ ROI manager allowed us to define five regions of interest;olfactory, turbinate, esophagus, base and vestibule which werequantitatively analyzed with each device administration. The regions aredefined by the lines seen in FIG. 22 and these regions contain aspecific area, in pixels that can be quantitated based on the signalintensity of the fluorescein. FIG. 22 also shows a typical spray patternafter a POD administration. The fluorescein administered into the modelby the POD device can be seen as the dark intensity on the lightbackground. It can be noted from in FIG. 22 that a majority of theadministered dose resides within the olfactory region of the human nasalmodel. Each pixel within these photos can possess a value of 0 to 255.The Measure function of ImageJ calculates the mean pixel value over eachdefined region of interest. The total signal recorded within aparticular region of interest is therefore the product of the mean pixelvalue by the number of pixels measured. Of additional interest is thereported Max value. Because the photo cannot record more than 256 levelsof signal, we conclude that the assay is not valid if we receive valuesof 255 in that column, because we cannot be sure if the actual signal isnot significantly greater than 255 if it could be measured. Such asituation would have the effect of underreporting signal in that ROIbecause the signal is effectively clipped. For this reason, the cameraexposure settings are critical to ensure that the signals recorded fallwithin the sensitivity range of the method yet allow for the maximalsensitivity of the method as well.

In addition, our calculations involved the subtraction of valuesobtained from a blank recording. This is because there is some straylight leakage and always therefore the potential for backgroundfluorescence involving the model and the imitation mucus. Because theseelements are not perfect in application, we do a background photo recordeach time and do a subtraction for each data point. This method offersthe advantage of providing fractional deposition on more than one regionof the nasal model. It also offers clear qualitative photo/visualconfirmation of the quantitative results.

The results of a deposition study are shown in Table 3. Two differentPOD devices were used and are referred to as Tip #1 and Tip #2. Each Tipwas administered into the nasal model N=3 times at either 0 degreeshorizontal angle with respect to the septum or 5 degrees horizontallytowards the septum. All POD administrations were administered at avertical angle of 55 degrees with respect to the base of the nasalcavity.

Table 3 Tip #1 Tip #1, 0 degrees 5 degrees anterior Zone Ave Distrib.Std. Dev. Ave Distrib. Std. Dev Olfactory 59.9 14.7 70.0 12.9 Turbinate38.3 13.2 35.1 5.3 Esophagus −1.4 4.7 −3.1 12.1 Base 3.6 4.1 0.7 2.5Vestibule −0.4 4.6 −2.7 2.8 Tip #2, Tip #2, 0 degrees 5 degrees anteriorZone Ave Distrib. Std. Dev. Ave Distrib. Std. Dev Olfactory 58.2 3.961.1 7.3 Turbinate 49.1 12.1 38.5 3.6 Esophagus −4.6 5.2 −0.1 4.6 Base−0.8 1.5 0.8 0.1 Vestibule −1.9 3.4 −0.4 2.3

Example 3

Impaction force testing was used to compare several nozzle/dose chamberconfigurations with MDI drivers to several commercial nasal sprayproducts. Impact impaction force is an ideal method to characterizeplume characteristics that are important for dose delivery consistency,dose localization and dosing comfort and safety. A schematic of theexperimental setup used in this example is shown in FIG. 23 .

Impaction force measurements were carried out on a Mettler Toledo XS 64with data output set at 10 per second coupled to an Apple MacBook Pro2.2 GHz Intel Core 2 Duo processor, 4 GB 667 MHz DDR2 SDRAM via a ft.RS232 (Mettler Toledo) to USB cable (Gigaware) with supporting driversoftware. Data acquisition was carried out using Windmill Logger version4.07, release 7 (Windmill Software Ltd.) in a Windows Vista virtualmachine environment using Parallels Desktop 5 for Mac on the MacBookPro. Data collected via Windmill Logger was imported directly intoMicrosoft Excel for graphical processing and analysis.

An impaction force stage was constructed to perform the measurements.This stage included means for accurate level and distance controls alongwith customized holders for the individual devices tested. Actuation wascarried out manually. POD or commercial devices were aligned to impactthe direct center of a 16.9 gram aluminum pan, 74 mm×80 mm. The pan wascleaned of dose/debris between each data shot. The distance from nozzleaperture to pan was 4 cm, consistent with the conclusions of Guo, et al.2009 (Guo, J Phann Sci., 2009, August; 98(8):2799-806.) as being withinthe 3 cm to 6 cm window of distances that generate the highest impactionforces and also consistent with our target distances in human nasalmodels. MDI triggered values obtained via valve actuation as tested wasbroadly insensitive from shot to shot when used as directed. The onlyeffects seen were lower values if actuated very slowly.

Three commercial nasal spray products were tested in this Example: RiteAid Pump Mist Nasal relief, oxymetasoline HCL 0.05%; NeilMed NasoGel ForDry Noses, Saline gel spray; and Rite Aid NoDrip Nasal Spray, pump,oxymetazoline, 0.05%.

The device used in this study is shown in FIG. 3 and is referred to as apressurized olfactory delivery (POD) device in this Example. The PODnozzle was compared to the commercial spray pumps tested above. In thisExample we tested the POD device under the same parameters as thecommercial sprays using MDI canisters loaded with a 5% Ethanol,fluorescein mixed with either HFA 134a or HFA 227. The MDI valves wereset to deliver a fixed volume of 50 uL.

The impaction forces measured for three commercial pump style nasalsprays were found to generate peak forces generally below 0.8 grams.These products are noted for either generating very broad spray patternsor slow moving streams of gelatinous material. The forces generated fromthese tested products fall well below the forces quoted by Guo et al.,2009 of 3.0 to 4.9 grams. The POD device generated impaction forcemeasurements with peaks near 4 grams with an average of just below 3grams of force when the more highly volatile HFA 134a was used. Thisforce dropped to below 2 grams when HFA 227 was used instead. In eithercase, the impaction forces for the POD device also fell well within therange of impaction forces measured for commercial MDI device by Guo etal., 2009, which showed a maximum value of 6.5 grams.

It was found that the impaction forces measured are affected by the HFAtype used and the volume of HFA dispensed by the MDI canister. Also thedose chamber and nozzle configuration have impacts on impaction forces.In no case have we measured forces greater than that measured for theone commercial product referenced in the Guo et al. paper.

Example 4

In this example the device, referred to as a pressurized olfactorydelivery (POD) device, was tested to determine if the device wouldrelease a cold temperature spray. This testing involved the measurementof surface temperature changes on the target region caused by HFA POD. Aschematic of the experimental setup used in this example is shown inFIG. 24 .

The hydrofluoroalkane (HFA) used as a propellant in the POD device isreleased from the metering can as a liquid. Very quickly after releasethe HFA vaporizes and expands to form the pressure impulse that drivesthe dose through the POD nozzle. It is also a characteristic of the HFAPOD that the HFA gas is expelled toward the target 2400 along with andafter the dose is delivered. The expansion of the HFA causes a markeddrop in temperature of the propellant gas during the firing process. Inorder to establish whether this temperature drop is transferred totarget tissues and to what extent, we designed and performed experimentsto detect and measure the surface temperature of targets during andimmediately after they were impacted by the device while only releasingHFA or while releasing a mixture of HFA and liquid compound (as it wouldbe used for administering a liquid drug product).

Materials: Kintrex infrared thermometer 2402, model IRT0421, capable ofmeasuring surface temperature without actually contacting the surfacebeing tested. Temperatures are reported in degrees Fahrenheit. Anactuator fitted with a HFA 134a canister designed to deliver 50 uL ofpropellant, Kimwipe paper wipes, petri dish 2404, 1% agarose/water 3tips, including a high impedance, low impedance nozzle and openconfiguration/absent frit.

FIG. 24 illustrates the experimental setup for measuring temperaturechanges during the firing of the POD device under different conditions.The thermometer 2402 was positioned 4 cm from the target 2400. At thatdistance the thermometer 2402 “sees” and reads from a circular spot of0.33 cm diameter 2406 (target circle in FIG. 24 ).

Three tip configurations were tested. 1. A tip with a high impedancenozzle fitted. A high impedance nozzle is sufficiently restrictive toflow of HFA gas that the nozzle is the limiting feature of the PODsystem. It releases gas over a longer duration. 2. A tip with a lowimpedance nozzle fitted. In this tip, the frit, near the actuator end ofthe tip is actually the limiting feature of the device. It releases gasfaster than the high impedance nozzle. 3. A tip that contains neither anozzle nor frit. This tip offers essentially no restriction to HFA gasor liquid flow through the device. With these three configurations, weexpected to understand how restrictions on gas flow affects thetemperature of target 2400 upon firing and also define the distinct rolethat the teflon frit plays in diffusing and facilitating the transitionof FIFA from the liquid state to the gaseous state.

We also tested the effect of target proximity to the nozzle with respectto temperature changes experienced by the target 2400. We fired from adistance of 4 cm and 2 cm.

In addition, we fired the device at three different targets. 1) We useda very low mass target 2400. This target 2400 was constructed of aKimwipe tissue paper. We anticipated that a low mass target would have avery low thermal inertia and therefore would display much more change intemperature upon firing. 2) We created a mock epithelium (epitheliummimic #1) by overlaying a Kimwipe tissue paper wipe onto 1%agarose/water. This was designed so that the thermometer 2402 wouldreact to a similar color and texture surface as the low mass target. 3)Another mock epithelium (epithelium mimic #2) made from 1% agarose/waterwith Kimwipe paper embedded just below the surface (less than 0.5 mm) ofthe agarose. This target 2400 was designed in case the thermometer 2402would react to the paper layer just below the essentially clear agaroseto see if the temperature effects were mostly superficial.

In addition, some temperature measurements were done on the epitheliummimics when a 50 μL, water dose was added to the setup. Table 4summarizes the temperature changes detected upon the firing of onlyhydrofluoroalkane propellant. The temperature change in degreesFahrenheit is represented by the symbol A. We believed and confirmedthat this would create the conditions for the most dramatic temperaturechanges. With the low mass, low thermal inertia paper target, thegreatest temperature change was when no frit or nozzle was installed inthe tip. The data for this condition was closely clustered near −25° F.Indeed, with this setup particulate or mist can be seen ejecting fromthe end of the tip, suggesting that a certain fraction of the HFAremains liquid through its transit through the actuator body and tip.Any liquid HFA that were to reach the target 2400 would then ablate onthe target 2400 and could explain the dramatic temperature drops seen.

TABLE 4 Low Impedance Nozzle 4 cm target 2 cm target No Frit/Nozzle -Δ-ΔMax -Δ -ΔMax -Δ -ΔMax Low Mass 2.5 3.7 4.4 5.6 25.2 27.2 epithelium0.5 1.1 1.1 1.9  3.9  4.4 mimic #1 epithelium 1.0 1.5 0.9 1.8  4.2  5.3mimic #2 High Impedance Nozzle 4 cm target 2 cm target No Frit/Nozzle -Δ-ΔMax -Δ -ΔMax -Δ -ΔMax Low Mass 1.9 3.2 2.9 5.2 25.2 27.2 epithelium1.2 3.5 1.2 1.6  3.9  4.4 mimic #1 epithelium 1.7 2.6 2.5 3.2  4.2  5.3mimic #2

In contrast, all other experimental conditions resulted m far smallertemperature drops at the target. Modest drops of 3-4° F. were seen withthe unobstructed tip on the epithelium mimics. It is clear the thermalcapacity of the target is critical in this analysis.

Inclusion of the Teflon frit and nozzle into the tip resulted in evensmaller temperature drops. Against the low mass tissue target, the lowimpedance nozzle resulted in the greatest temperature drop, with amaximum value of 5.6° F. at a distance of 2 cm. The high impedancenozzle resulted in slightly lower temperature drops. Typical values were3° F. or less.

There is a slight trend depending on tip distance to target. As would beexpected, shots at closer range can result in lower temperatures at thetarget.

When a dose load of 50 μL water was added to the tip that included aTeflon frit and low impedance nozzle very small temperature effects wereseen. The data ranged from a 0.5° F. drop to a 0.2° F. increase. It wasdetermined that with the small changes seen and the difficulty ofhandling the liquid doses in the experimental setup that we would not beable to get reliable data with liquid doses. However we believe the datacollected with the liquid doses in consistent with predicted outcomes.

The hydrofluoroalkane propellant used in the POD device will have veryminimal effects on the temperature of impacted tissues. The data showthe Teflon frit's function in the POD and the decrease in thetemperature of the impacted site when only HFA is delivered. Inaddition, a typical load of 50 μL will itself likely reduce anytemperature effects.

Example 5

In assaying the targeting of the human olfactory region with a drugproduct, 2 formulations of 2-PAM were delivered from the device into ahuman nasal cavity model and analyzed for olfactory deposition.

A silicon rubber human nasal cavity model was purchased from Koken Inc.(Tokyo, Japan). A trace amount (0.1%) of Coomassie blue (SigmaAldrich,St. Louis, Mo.) was mixed into the dry powder 2-PAM. The dry powder2-PAM and Coomassie blue were crushed to a homogenous powder with amortar and pestle. 0.1% rhodamine B was added into the aqueousformulation (250 mg/ml) for visualization within the nasal cavity model.The dry powder formulation was sprayed into the model nasal cavity(N=10) with the device and pictures were taken to get a qualitativemeasure of deposition in the olfactory region. The pictures were judgedas to whether a majority of the powder 2-PAM was deposited in theolfactory region.

The same was done with the aqueous formulation, and the deposition inthe olfactory region was also quantified by weight for this formulation(N=10). The olfactory region of the nasal cavity model was cut from themodel so that it was removable. The olfactory region was weighed beforethe POD spray and after the spray and the percent of dose administeredto the olfactory region was calculated by weight.

The dry powder 2-PAM formulation administered into the human nasalcavity was effective in depositing of drug in the olfactory region.Qualitative examination of 10 administration attempts into the modelconsistently was judged to show a majority of drug (about 50% orgreater) in the olfactory region. In addition to depositing drug on theolfactory region, the dry powder POD device deposited a substantialamount of the 2-PAM dose at the interface with the cribriform plate areaof the model which separates the olfactory region of the nasal cavityfrom the brain.

The aqueous 2-PAM formulation displayed similar patterns of depositionin the human nasal cavity model as the dry powder formulation. Inaddition to the qualitative photos of the human nasal cavity, 62.6±9.6%of the dose was determined to deposit in the olfactory region of thenasal cavity.

The present invention is not to be limited m scope by the specificembodiments described herein. Indeed, various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description and accompanyingfigures. Such modifications are intended to fall within the scope of theappended claims.

What is claimed is:
 1. A device for delivery of a compound to a nasalcavity, the device comprising: an air compression chamber; a manualpressure actuator that causes air to be released from the aircompression chamber upon actuation; a diffuser in communication with theair compression chamber; a drug chamber in communication with thediffuser and a diffusion tube, the drug chamber configured to hold thecompound and the diffusion tube allowing for the released air to bypassthe compound; and a nozzle in communication with the drug chamber,wherein air released from the air compression chamber is configured toflow through the diffuser to contact and propel the compound out of thenozzle forming a plume.
 2. The device of claim 1, wherein the manualpressure actuator further comprises a lock pin, wherein the lock pin isconfigured to maintain high pressure air in the air compression chamber.3. The device of claim 1, further comprising a trigger valve incommunication with the air compression chamber such that when thetrigger valve is rotated from an open state to a closed state, air inthe air compression chamber is blocked from contacting the diffuser andpropelling the compound out of the nozzle.
 4. The device of claim 1,wherein the manual pressure actuator comprises a piston.
 5. The deviceof claim 1, wherein the manual pressure actuator comprises a syringe. 6.The device of claim 1, wherein the manual pressure actuator comprises asyrette.
 7. The device of claim 1, wherein the diffuser isheterogeneously porous or homogenously porous.
 8. The device of claim 1,wherein the compound is a drug or diagnostic agent.
 9. The device ofclaim 8, wherein the diagnostic agent is an imaging agent.
 10. Thedevice of claim 1, wherein the diffuser is porous, the porous diffuserbeing a disk-shaped member including at least one conical shaped memberhaving a distal aperture.
 11. The device of claim 1, wherein thediffuser is configured to act as a one-way check valve.
 12. The deviceof claim 1, wherein the diffuser extends into the compound in the drugchamber.
 13. A device for delivering a compound to a nasal cavity, thedevice comprising: an air compression chamber; a manual pressureactuator comprising a lock pin, the manual pressure actuator configuredto release air from the air compression chamber, the lock pin configuredto maintain high pressure air in the air compression chamber; a triggervalve configured to be in communication with the air compression chambersuch that when the trigger valve is rotated from an open state to aclosed state, air in the air compression chamber is blocked from exitingthe air compression chamber; a diffuser in communication with thetrigger valve; a drug chamber in communication with the diffuser and adiffusion tube, the drug chamber configured to hold the compound and thediffusion tube allowing for the released air to bypass the compound; anda nozzle in communication with the drug chamber, wherein air releasedfrom the air compression chamber is configured to flow through thediffuser to contact and propel the compound out of the nozzle forming aplume.
 14. The device of claim 13, wherein the manual pressure actuatorfurther comprises a piston.
 15. The device of claim 13, wherein themanual pressure actuator further comprises a syringe.
 16. The device ofclaim 13, wherein the manual pressure actuator further comprises asyrette.
 17. The device of claim 13, wherein the diffuser isheterogeneously porous or homogenously porous.
 18. The device of claim13, wherein the diffuser is configured to act as a one-way check valve.19. The device of claim 13, wherein the diffuser is porous, the porousdiffuser being a disk-shaped member including at least one conicalshaped member having a distal aperture.
 20. The device of claim 13,wherein the diffuser extends into the compound in the drug chamber.